{"doi":"10.3389/fnmol.2024.1433981","title":"Molecular determinants of resurgent sodium currents mediated by Navβ4 peptide and A-type FHFs","abstract":"Introduction Resurgent current ( I NaR ) generated by voltage-gated sodium channels (VGSCs) plays an essential role in maintaining high-frequency firing of many neurons and contributes to disease pathophysiology such as epilepsy and painful disorders. Targeting I NaR may present a highly promising strategy in the treatment of these diseases. Navβ4 and A-type fibroblast growth factor homologous factors (FHFs) have been identified as two classes of important I NaR mediators; however, their receptor sites in VGSCs remain unknown, which hinders the development of novel agents to effectively target I NaR . Methods Navβ4 and FHF4A can mediate I NaR generation through the amino acid segment located in their C-terminus and N-terminus, respectively. We mainly employed site-directed mutagenesis, chimera construction and whole-cell patch-clamp recording to explore the receptor sites of Navβ4 peptide and FHF4A in Nav1.7 and Nav1.8. Results We show that the receptor of Navβ4-peptide involves four residues, N395, N945, F1737 and Y1744, in Nav1.7 DI-S6, DII-S6, and DIV-S6. We show that A-type FHFs generating I NaR depends on the segment located at the very beginning, not at the distal end, of the FHF4 N-terminus domain. We show that the receptor site of A-type FHFs also resides in VGSC inner pore region. We further show that an asparagine at DIIS6, N891 in Nav1.8, is a major determinant of I NaR generated by A-type FHFs in VGSCs. Discussion Cryo-EM structures reveal that the side chains of the critical residues project into the VGSC channel pore. Our findings provide additional evidence that Navβ4 peptide and A-type FHFs function as open-channel pore blockers and highlight channel inner pore region as a hotspot for development of novel agents targeting I NaR .","journal":"Frontiers in Molecular Neuroscience","year":2024,"id":469382,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":395092,"name":"Yanling Pan","orcid":"0000-0002-0915-2639","position":1,"is_corresponding":false},{"id":1302711,"name":"Jingyu Xiao","orcid":"0000-0002-6961-7397","position":2,"is_corresponding":false},{"id":276991,"name":"Theodore Cummins","orcid":"0000-0001-9509-6380","position":3,"is_corresponding":false},{"id":395093,"name":"Yucheng Xiao","orcid":"0000-0002-0298-7158","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:05:28.027781Z","pmid":"39416265","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}